期刊
CELL REPORTS
卷 3, 期 1, 页码 211-222出版社
CELL PRESS
DOI: 10.1016/j.celrep.2012.11.023
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资金
- National High Technology Research and Development Program of China [2006AA02Z4B5]
- NSFC [81272451/H1609, 81070033/H0108, 30770835]
- Key Projects from Guangdong NSF [9251018201002, 10A057S]
- Guangzhou Education Commission
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL072166, R01HL085629] Funding Source: NIH RePORTER
Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.
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